NDUFAF5, also known as C20orf7, is a mitochondrial complex I (CI) assembly factor. It belongs to the family of seven-β -strand S -adenosylmethionine -dependent methyltransferases and hydroxylates Arg-73 in the NDUFS7 subunit of human complex I at an early stage in the assembly of complex I, which is crucial for mitochondrial respiratory chain function [2,4].

Mutations in NDUFAF5 are linked to Leigh syndrome, presenting phenotypic heterogeneity. The onset age has a bimodal distribution. The early-onset group (age < 3 years) shows psychomotor delay, seizure, respiratory failure, and hyponatremia, while the late-onset group (age ≥ 5 years) has normal development initially but then develops slowly progressive dystonia. Bilateral basal ganglia necrosis is a common radiological feature, with more brainstem and spinal cord involvement in early-onset patients. A modifier gene analysis shows a higher concomitant mutation burden in early-onset compared to late-onset cases with the p.Met279Arg variant, consistent with more impaired mitochondrial function in early-onset fibroblasts [1]. In addition, NDUFAF5-related disorders can also present with prenatal manifestations such as brain cysts, corpus callosal malformations, non-immune hydrops fetalis, and growth restriction [3].

In conclusion, NDUFAF5 is essential for the assembly of mitochondrial complex I. Research on NDUFAF5-related disorders, especially through studying the phenotypic heterogeneity in patients with its mutations, helps understand the role of NDUFAF5 in mitochondrial function and the pathogenesis of Leigh syndrome and other related diseases [1,3].

References:

1. Chen, Pin-Shiuan, Lee, Ni-Chung, Sung, Chieh-Ju, Hwuh, Wuh-Liang, Lin, Chin-Hsien. 2023. Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5. In Movement disorders : official journal of the Movement Disorder Society, 38, 2217-2229. doi:10.1002/mds.29604. https://pubmed.ncbi.nlm.nih.gov/37752895/

2. Carilla-Latorre, Sergio, Annesley, Sarah J, Muñoz-Braceras, Sandra, Fisher, Paul R, Escalante, Ricardo. 2013. Ndufaf5 deficiency in the Dictyostelium model: new roles in autophagy and development. In Molecular biology of the cell, 24, 1519-28. doi:10.1091/mbc.E12-11-0796. https://pubmed.ncbi.nlm.nih.gov/23536703/

3. Brabbing-Goldstein, D, Kozlova, D, Bazak, L, Birnbaum, R, Yaron, Y. . Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype. In Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology, 63, 392-398. doi:10.1002/uog.27482. https://pubmed.ncbi.nlm.nih.gov/37718619/

4. Rhein, Virginie F, Carroll, Joe, Ding, Shujing, Fearnley, Ian M, Walker, John E. 2016. NDUFAF5 Hydroxylates NDUFS7 at an Early Stage in the Assembly of Human Complex I. In The Journal of biological chemistry, 291, 14851-60. doi:10.1074/jbc.M116.734970. https://pubmed.ncbi.nlm.nih.gov/27226634/